Major depression is the leading cause of disability among Americans between the ages of 15 and 44 and is one of the top ten causes of morbidity and mortality worldwide. Current treatments are well tolerated but can lead to less than 50% remission rates among patients. Due to the fact that most antidepressant drugs act by increasing extracellular levels of serotonin (5-HT), it has been hypothesized that decreased levels of 5-HT might underlie major depressive illness. However, this theory has been difficult to test in a preclinical setting due to a lack of hyposerotonergic mouse models. The tryptophan hydroxylase 2 R439H knock-in mouse (Tph2KI) provides a novel system in which the consequences of chronic 5-HT deficiency can be examined. This mouse exhibits an 80% reduction in brain 5-HT as the result of a mutation in Tph2, the enzyme responsible for brain 5-HT synthesis. In addition, these mice recapitulate several physiological features often associated with depression, including inhibited prolactin secretion and hypothermic responses to serotonergic activation, and decreased levels of the 5-HT metabolite, 5-HIAA. Because of these physiologic parallels to the human condition, Tph2KI mice represent a highly relevant, naturalistic rodent model for studying the impact of low levels of 5-HT on cell biological processes and behaviors related to depression and antidepressant action. Work from the past decade has demonstrated that elevation of 5-HT promotes neurogenesis and has revealed a requirement for neurogenesis in several antidepressant-like effects in mice. Elevation of 5-HT using antidepressant drugs can also prevent the inhibition of neurogenesis and the depressive-like behaviors induced by exposure of rodents to chronic stress. However, whether decreased levels of 5-HT lead to impaired neurogenesis, altered antidepressant-like responses, or increased vulnerability to stress has not been determined. The proposed research will test the hypothesis that chronic 5-HT deficiency will lead to inhibition of baseline adult hippocampal neurogenesis, diminished responses to antidepressant drugs, and decreased resilience to chronic stress. This hypothesis will be evaluated through the performance of three specific aims: 1) To examine the effects of hyposerotonergia on baseline hippocampal neurogenesis. 2) To determine the neurogenic and behavioral responses of 5-HT deficient mice to antidepressants. 3) To study the neurogenic and behavioral consequences of chronic stress in Tph2KI mice. These experiments will provide some of the first experimental evidence regarding the impact of chronic hyposerotonergia on adult neurogenesis, antidepressant responses, and vulnerability to stress. The data obtained from the proposed study will address several prominent depression theories, including the Serotonin Deficiency, the Neurogenesis Deficiency, and the Diathesis-Stress Hypotheses of depression and may shed light on the pathophysiology underlying depressive-like states.